It had been shown previously that MRL+/+ mice exposed to occupationally relevant doses of the environmental contaminant trichloroethylene in their drinking water developed lupus-like symptoms and autoimmune hepatitis in association with activation of Interferon-gamma (IFN-gamma)-producing CD4+ T cells. Since trichloroethylene must be metabolized in order to promote the T-cell activation associated with autoimmunity, the present study was initiated to determine whether the immunoregulatory effects of trichloroethylene could be mimicked by one of its major metabolites, trichloroacetaldehyde (TCAA). At concentrations ranging from 0.04 to 1 mM TCAA co-stimulated proliferation of murine T-helper type 1 (Th1) cells treated with anti-CD3 antibody or antigen in vitro. TCAA at similar concentrations also induced phenotypic alterations commensurate with activation (upregulation of CD28 and downregulation of CD62L) in both cloned memory Th1 cells, as well as naïve CD4+ T cells from MRL+/+ mice. TCAA-induced Th1 cell activation was accompanied by phoshorylation of activating transcription factor 2 (ATF-2) and c-Jun, two components of the activator protein-1 (AP-1) transcription factor. TCAA at higher concentrations was also shown to form a Schiff base on T cells, and inhibition of Schiff base formation suppressed the ability of TCAA to phosphorylate ATF-2. Taken together, these results suggest that TCAA promotes T-cell activation via stimulation of the mitogen-activated protein (MAP) kinase pathway in association with Schiff base formation on T-cell surface proteins. By demonstrating that TCAA can stimulate T-cell function directly, these results may explain how the environmental toxicant trichloroethylene promotes T-cell activation and related autoimmunity in vivo.